Challenge AwardsTwo- to three-year grants for established investigators

Julie’s Hope Award

Brian Litt, MDUniversity of Pennsylvania

"Flexible, Active, Implantable Devices for Epilepsy"

Dr. Litt and his coworkers developed a new implantable brain device to map, analyze and control epileptic networks on a much finer scale than has previously been possible. The new devices contain thousands of high-resolution sensors and "effectors" that can measure electrical, optical and other signals in brain tissue over clinically relevant scales. The devices are built on dissolvable materials that cause them to closely adhere to the brain’s irregular surface. With funding from CURE, they will further develop these devices and test them first in animal models and then in individuals with medically resistant epilepsy in pursuit of CURE’s mission to achieve "no seizures and no side effects."

Dravet Syndrome Foundation & CURE Award

Scott Baraban, PhDUniversity of California, San Francisco

"Gene Profiling and High-Throughput Drug Screening in a Zebrafish Model of Dravet Syndrome"

Pediatric epilepsies are associated with developmental or cognitive co-morbidities and are not well controlled by available drugs. Unfortunately, existing drug discovery programs are not designed to address this problem, as they are primarily based on acute or acquired seizures in adult rodent models of the epilepsies. Dr. Baraban seeks to shift current research in the epilepsy field in two ways. First, by utilizing immature zebrafish models designed to mimic known single-gene mutations seen in children (for example, Dravet syndrome), he will establish a drug discovery program targeted at pediatric epilepsy that also incorporates large-scale microarray gene analysis. Second, by focusing on the zebrafish model, he will establish a new template for high-throughput cost-effective drug screening with distinct advantages over current rodent-based approaches.

Sacha D. Nelson, MD, PhDBrandeis University

"Acquired Interneuronopathy in a Mouse Model of Infantile Spasms"

Infantile spasms (IS) is a devastating form of childhood epilepsy, which is difficult to treat and often has a poor prognosis. In order to better understand the underlying mechanism(s) that cause IS, two paradoxically opposite animal models have been proposed. In one model, inhibitory interneurons fail to integrate properly into the cortex, leading to too much excitation and too little inhibition. In the other model, blocking excitation with a toxin for several days leads to epilepsy when the toxin wears off. Dr. Nelson will explore the hypothesis that blocking normal activity causes a secondary change in interneurons, impairing cortical inhibition. Studies of biochemical changes within these interneurons may provide new targets for pharmacological treatments to prevent or treat IS and related childhood disorders.

"Silencing Hyperactive Neurons as a Treatment for Temporal Lobe Epilepsy"

Imagine a day when focal and temporal lobe epilepsies can be cured by gene therapy. Imaging techniques already allow us to localize seizure foci; however, incremental advances in drug design and epilepsy surgery are unlikely to precisely target epileptic tissue. The goal of Drs. Perez-Reyes and Kapur’s research is to develop a novel gene therapy tool that will silence hyperactive neurons that cause seizures by selective expression of a potassium leak channel. Proof-of-principle studies will be performed in rodent models of temporal lobe epilepsy. To accelerate translation of this technology to treating individuals with epilepsy, expression of the channel will be drug inducible, allowing control of seizures while minimizing possible side effects.

Prevention of Epilepsy After Brain Injury AwardTwo- to three-year grants in support of research preventing or treating post-traumatic epilepsy

Post-traumatic epilepsy is a growing health issue due to the increasing incidence of brain trauma in both the civilian and military populations, and the increased risk for developing epilepsy even many years after the brain injury. Activation of immune responses is an integral part of the brain’s response to injury. Dr. Santhakumar’s research will focus on a class of innate immune receptors known to regulate neuronal growth and excitability and determine their contribution to hippocampal structural and functional changes after brain injury. The studies will identify the cellular interactions that mediate innate immune responses following brain trauma and test whether modulation of the immune response can reduce the risk for developing epilepsy following brain injury.

Hypoxia-ischemia (HI) is the most common cause of neonatal seizures and often results in long-term neurological problems. Current first-line drugs to treat seizures in these children are not effective and are associated with significant side effects. Potassium channels play an important role in controlling brain excitability during early life. Dr. Raol’s project will examine whether a potassium channel opener (flupirtine) can treat HI-induced neonatal seizures and alter long-term adverse neurological outcomes in an animal model of HI. This medication has been in clinical use in Europe for decades and, if successful, these studies could rapidly translate into a new effective treatment for neonatal seizures caused by HI and a better understanding of the underlying mechanisms of epilepsy in these children.

Multidisciplinary AwardTwo- year grants in support of collaborative research

The goal of Drs. Patel and Roberts’s study is to determine the role of gamma-ketoaldehydes in cognitive impairment associated with chronic epilepsy. Gamma-ketoaldehydes are highly reactive products of lipid (fat) oxidation that bind to and crosslink proteins and DNA. They will utilize a multidisciplinary approach to determine if gamma-ketoaldehyde formation occurs in a model of chronic epilepsy and whether pharmacological scavenging of gamma-ketoaldehydes inhibits cognitive decline and/or the development of epilepsy. These studies could lead to the development of novel gamma-ketoaldehyde scavengers for the treatment of cognitive dysfunction associated with acquired epilepsy.

Seizure-induced respiratory (breathing) dysfunction is thought to contribute to Sudden Unexpected Death in Epilepsy (SUDEP). The KCNQ family of potassium channels are important determinants of neuronal excitability, and mutations in KCNQ genes can lead to pediatric epilepsy and SUDEP. Drs. Mulkey and Tzingounis hypothesize that KCNQ channels are required for proper control of chemoreceptor activity (i.e., neurons that drive breathing). They propose that disruption of KCNQ channel activity creates a background of respiratory problems that may worsen during seizures and contribute to SUDEP. They will investigate contributions of KCNQ channels to the firing behavior of chemoreceptor neurons. Understanding the role of KCNQ channels in regulating chemoreceptor activity may lay the foundation for the development of new treatments and diagnostic tests to identify individuals at risk for SUDEP.

The 2011 Christopher Donalty and Kyle Coggins Memorial Award

Jack Parent, MD & Lori Isom, PhDUniversity of Michigan

"Cardiac Mechanisms of SUDEP in Dravet Syndrome"

Dravet Syndrome (DS) is a severe childhood epilepsy usually caused by mutations in a sodium channel gene, SCN1A, that is critical for nerve cell function. Sudden Unexpected Death in Epilepsy (SUDEP) is a major concern and risk for individuals with DS. Because SCN1A is also active in heart cells, Drs. Parent and Isom hypothesize that SCN1A mutations increase SUDEP risk by causing heart rhythm disturbances. To directly study heart cells from individuals with DS, they are using the induced pluripotent stem cell (iPSC) method in which skin cells from an individual with DS are reprogrammed to become stem cells, and then the cells are turned into heart cells. The study of heart cells derived from individuals with DS should provide critical clues about SUDEP mechanisms, and will offer a useful model system to test new therapies.

Innovator AwardsOne-year grants in support of the exploration of a highly innovative new concept or untested theory that addresses an important problem relevant to epilepsy

Robert Gross, MD, PhDEmory University

“Septohippocampal Stimulation for Seizures and Memory”

Memory loss is a major contributor to disability for individuals with seizures arising from the mesial temporal lobe of the brain. Dr. Gross will test whether electrical stimulation of an important nerve pathway, the septohippocampal system, which connects the frontal lobe to the temporal lobe, can both control seizures and improve memory. Electrical stimulation will be done using an animal model of hippocampal epilepsy, a valid model of epilepsy that also shows memory dysfunction similar to that found in individuals with epilepsy. Positive results would pave the way for a clinical pilot study of electrical stimulation in individuals with mesial temporal lobe epilepsy as a means to control seizures and improve memory.

Quoc-Thang Nguyen, PhD & Thomas Fouquet, PhDNeurAccel Biosciences

“Novel Technology to Detect Neurotransmitters During Seizures”

Epilepsy is strongly linked to a chemical imbalance in the brain and many anticonvulsant drugs restore the normal contribution of neurotransmitters (chemicals) to allow the brain to function. However, the role of neurotransmitters in epilepsy is poorly understood. To address this problem, Dr. Nguyen and his collaborator Dr. Fouquet will use biophotonics technology to measure levels of the neurotransmitter acetylcholine in the brains of experimental animals undergoing seizures to better understand the involvement of neurotransmitters in epilepsy and to establish specific neurotransmitters as biomarkers that could predict the onset of seizures. The results of this research will be important in the design of novel compounds to cure epilepsies that currently resist treatment with available anticonvulsant medications.

Pyridoxine-dependent epilepsy (PDE) is a rare genetic disorder causing seizures due to errors in a specific gene, which damage a protein called “antiquitin.” PDE occurs in 1 in 100,000 to 700,000 individuals worldwide, with at least 100 cases reported. Current treatment, relying on dietary supplements of pyridoxine, does not offer a complete solution. Paula Waters, together with co-investigators Marion Coulter-Mackie and Sylvia Stockler, is working toward an innovative new treatment for PDE. Their aim is to decrease the effects of genetic errors on the antiquitin protein by first doing studies to understand how genetic errors affect the structure and function of the antiquitin protein. Second, they will determine whether these consequences can be reversed by identifying so-called “molecular chaperones,” which can rescue the protein. If successful, this method may open the door to treating other types of rare genetic epilepsies.

Up to 40% of individuals with epilepsy continue to have seizures. To improve the treatment of these individuals, Dr. Ma developed a new imaging technique that can provide high resolution mapping of the seizure focus to guide the neurosurgeon during surgery. The CURE-funded research will focus on the relationship between the electrical aspect of seizure onset and spread of the seizures to other brain areas, as well as the changes in blood flow in the brain associated with seizures; both in the seizure focus and the surrounding normal brain. The new information provided by such a device, if used in clinical practice, could create a new paradigm in epilepsy mapping and dramatically increase the efficacy of surgery. Dr. Ma will also study the ability of the device to predict seizure onset before it begins and provide stimulation to the brain area to stop seizures.

Jeffery Tenney, MD, PhD Cincinnati Children’s Hospital Medical Center

“Seizure Generator Location and Antiepileptic Drug Efficacy”

Absence epilepsy is the most common type of pediatric epilepsy syndrome and up to half of children impacted fail the best initial treatment. Response to treatment may depend upon whether seizures begin on the surface of the brain or in deeper structures. The goal of Dr. Tenney’s research is to use state-of-the-art neuroimaging to compare areas of seizure onset in children with medication responsive and non-responsive epilepsy. This information will then be used to review the initial EEG for patterns that could predict treatment response. Better understanding of these differences will lead to reduced seizure burden and medication side effects.

Paulette McRae, PhD Children’s Hospital of Philadelphia

“Loss of the Perineuronal Net Component of the Extracellular Matrix after Status Epilepticus”

Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy and individuals who suffer from TLE can have impaired cognitive abilities that impact their ability to live a normal, productive life. The goal of Dr. McRae’s project is to understand how changes in the environment surrounding cells in the hippocampus contribute to learning and memory problems in individuals with TLE. The perineuronal net (PN) is a component of the extracellular environment that sheathes a subset of cells in the hippocampus. Preliminary work found that the PN is destroyed following an acute seizure. An enzyme will be used to breakdown the PN in the hippocampus, mimicking the PN loss observed after a seizure, in order to study changes in the extracellular environment that contribute to the destruction of the PN and the development of epilepsy. Dr. McRae will explore how these changes contribute to cognitive dysfunction associated with TLE.

Traumatic brain injury may result in activation of glial cells along with production of inflammatory molecules and damage to the blood-brain barrier; increasing the risk for the injured person to develop epilepsy. In experimental models of epilepsy, glia activation and blood-brain barrier breakdown contribute to seizure precipitation and recurrence. Using in vivo MRI and MRS imaging techniques combined with EEG analysis and behavioral testing in animals, Dr. Ravizza will evaluate whether blood-brain barrier damage and glia activation after brain injury predict the development of spontaneous seizures and cognitive dysfunction. This information may provide not only clinically relevant prognostic tools, but also novel targets for developing effective strategies to prevent seizures and/or cognitive dysfunction following traumatic brain injury.

Grants marked with an asterisk are made possible by individuals, families, foundations, or corporations.